The first synthesis of a Cinchona alkaloid or of a compound having the ring structure of a Cinchona alkaloid was that of Rabe and co-workers who synthesized the compound dihydroquinine. [See Ber., 64, 2487 (1931)]. The first total synthesis of a naturally occurring Cinchona alkaloid, quinine, was carried out by R. B. Woodward and W. von E. Doering, J. Am. Chem. Soc., 66, 849 (1944); id, 67, 860 (1945). This synthesis involved the reaction of dl-N-benzoylhomomeroquinene ethyl ester with ethyl quininate in the presence of sodium ethoxide. This condensation yielded dl-quinotoxine which, after cyclization, was smoothly reduced with sodium isopropoxide to yield a mixture of quinine and quinidine. Pure quinine was produced after resolution of the racemic mixture into its optical antipodes. More recently, two groups of workers have developed syntheses of quinine and related Cinchona alkaloids which are more adaptable to large scale production than the classical Woodward-Doering synthesis. Uskokovic and co-workers in J. Am. Chem. Soc., 92, 204 (1970) have reported a novel synthesis of quinine and quinidine involving the condensation of 6-methoxy lepidyl lithium with N-benzoyl-meroquinene methyl ester to yield a compound of the following structure (I). ##SPC1##
In a first route, reduction of this intermediate ketone with di-isobutylaluminumhydride yields a racemic alcohol which can be resolved by the use of dibenzoyl-(+)-tartaric acid to yield a compound of the following structure (II) wherein R" is methoxy and R'" is vinyl. ##SPC2##
Treatment of this intermediate alcohol with dilute acid eliminates the elements of water from the quinoline side chain to yield an intermediate propene (III) wherein R" and R'" have the same meaning as above. ##SPC3##
This propene spontaneously cyclizes to yield a mixture of desoxyquinine and desoxyquinidine (IV) wherein R" and R'" have the previous significance. ##SPC4##
Base catalyzed oxidation of the desoxyquinine-desoxyquinidine mixture yields, after separation by chromatography, quinine, quinidine, and a mixture of epiquinine and epiquinidine.
In a second route, the ketone (I wherein R" is methoxy and R'" is vinyl) is brominated on the methylene alpha to the quinoline ring. Reduction of the ketone group with sodium borohydride yields an intermediate bromohydrin which is readily converted to the epoxide (V) wherein R" and R'" have the same significance as before. ##SPC5##
Treatment of the epoxide with di-isobutylaluminumhydride yields the unacylated piperidine which spontaneously cyclizes to yield the quinuclidine alcohol derivative (a mixture of quinine, quinidine and the corresponding epi compounds when R" is methoxy and R'" is vinyl).
Uskokovic and co-workers also referred to the above synthetic procedure in an article appearing in J. Am. Chem. Soc., 93, 5904 (1971).
Gates and co-workers in an article appearing in J. Am. Chem. Soc., 92, 205 (1970) describe the condensation of N-acetyl-4-piperidineacetic acid ester with 6-methoxy lepidine to yield a ketone corresponding to Formula I above except that the benzoyl group on the piperidine nitrogen is replaced by a acetyl group. Reduction of the ketone to an alcohol and dehydration of the alcohol yields the N-acetyl derivative of the propane of formula III wherein R" is methoxy and R'" is vinyl. Hydrolysis of the acetyl group yields the intermediate (III) above which spontaneously cyclizes to give the desoxyquinine-desoxyquinidine mixture (IV). Gates et al. also applied the synthesis to compounds in which R" is methoxy and R'" is hydrogen to yield racemic 6-methoxyruban.
It is an object of this invention to produce the intermediates (III) and (V) by procedures which are relatively simple to carry out and which give greater yields of these intermediates than has heretofor been possible.